This application is in response to the NHLBI Participation in Research and Research Infrastructure "Grand Opportunities" (RC2) (RFA-OD-09-004). Translation of Fundamental Research Findings into Clinical Treatments for Heart, Lung, and Blood Diseases, 2) Phase II Clinical Trials Program of Novel Therapies for Heart, Lung, and Blood Diseases. SPECIFIC AIM. Atherosclerotic peripheral artery disease (PAD) of the lower extremities afflicts up to 5% of the U.S. population and is characterized by significant endothelial dysfunction. A lack of adequate sustainable therapies results in increased morbidity and mortality. In a Phase I study, we investigated mobilization of reparative bone marrow cells using granulocyte macrophage colony stimulating factor (GM-CSF) in patients with ischemic claudication. Compared to placebo, GM-CSF therapy was safe, mobilized progenitor cells into the circulation, and was associated with improvement in both endothelial dysfunction and treadmill exercise duration. The broad aim of this proposal is to translate these observations into new therapies for patients with severe PAD. Stimulation of bone marrow progenitor cells with colony stimulating factors, progenitor cell transplantation, and direct injection of bone marrow-derived cells appears to enhance re-endothelialization and neovascularization, and promote recovery in ischemic tissues in experimental models. We hypothesize that stimulation of progenitor cell release from the bone marrow will improve symptoms and outcomes in patients with PAD by either enhancing endothelial dysfunction or promoting development of functional collaterals, or both (Figure 1). To investigate whether mobilization of bone marrow-derived progenitor cells with GM-CSF improves symptoms of claudication in patients with PAD in a double-blind, placebo-controlled randomized Phase II study. The proposed study will be the first adequately powered, proof of concept Phase II double-blinded, placebo-controlled study to investigate whether mobilization of progenitor cells will improve outcomes in PAD, defining potential mechanisms of responses. Positive findings from this work will potentially lead to therapies that can be widely applied to treatment of intractable PAD and a definitive Phase III study. (End of Abstract)